As disclosed in WO 2007/126957, a genus of compounds as DGAT1-inhibitors, Including, at Example 5-1, the compound (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, having the structural formula (I):
and its sodium salt
may be employed in the treatment of a condition or a disorder such as inflammatory conditions, obesity, diabetes and related metabolic disorders.
Administration of such pharmaceutical agents via the oral route is preferred to parenteral administration because it allows self-administration by patients whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel. It is also important that dosage units which are manufactured and given to a patient have a high degree of uniformity in the amount of drug substance among the individual dosage units. In addition, the formulation must have a good dissolution profile and an optimal in-vivo drug-release profile with minimal unit-to-unit variability.
However, the compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular the sodium salt thereof, is a drug substance which is difficult to formulate due to its physicochemical properties. More particularly, the sodium salt of the compound of formula (I), depicted above as the compound of formula (II), is hygroscopic, poorly soluble and highly permeable, with a high moisture uptake at 95% relative humidity. It is also plate like, very fluffy, and sticky in nature. It also exhibits poor flow characteristics.
These characteristics of the drug substance make it particularly problematic to develop formulations comprising the compound of formula (II) which would be amenable to withstanding the compression forces required for a tablet form of the pharmaceutical composition with an adequate hardness window.
Furthermore, it is not trivial to make oral formulations of the compound of formula (II) in the form of tablets with the desirable required properties such as good flowability, compression behavior (e.g. no sticking during tablet compression), friability, and/or dissolution rate, in a reliable and robust way.
Accordingly, there is the need for a suitable and robust galenical formulation overcoming the above problems related to the properties of the compound of formula (II).
During the course of development, it has been found to be difficult to achieve such a formulation. The formulations of Example 1, for instance, were very sensitive to process parameters. It was found that compression at different hardnesses led to very different dissolution profiles. It was thus necessary to reduce the tablet to tablet variability of the drug release of the formulation, as this would have a major impact on the in-vivo availability of the drug. It was also necessary to develop a formulation which would be more robust to process parameters, and which would avoid one of the major problems associated with the compound of formula (II), i.e. its stickiness.